tbuckley/cabot-search huggingface dataset:
P740: PK, PD AND SAFETY OF FIRST-IN-HUMAN, FIRST-IN-CLASS PHASE I TRIAL (AUR103-101; BHARAT) OF AUR103, AN ORAL CD47 INHIBITOR, IN PATIENTS WITH ADVANCED MALIGNANCIES
Authors: Manjunath Krishnappa, Divyesh Mandavia, Minish Jain, Mukesh S, Ankit Patel, Anshul Agarwal, Sanjeev Giri, Nirbhay Kumar Tiwari, Saravanan Thiyagarajan, Mamon Dey, Gutta Padmanabha Naidu, Murali Ramachandra, Akhil Kumar
Journal: HemaSphere (2023)

Background: CD47 is a widely expressed receptor well known for its immunoregulatory functions. By interacting with its ligands, including signal regulatory protein α (SIRPα), it promotes escape of cellular phagocytosis of tumor cells by macrophages. AUR103 is an oral small molecule inhibitor of CD47 and is currently in a First in Human Phase 1 Trial (ClinicalTrials.Gov Identifier NCT05607199) Aims: To determine the Optimal Biological Dose (OBD) of single agent AUR103 by evaluating the overall safety, PK and PD of AUR103 in patients with relapsed advanced malignancies. Methods: This is an open-label, Multicentre, Phase I study being conducted in 3 + 3 design. Safety, PK and PD are being evaluated from each cohort, before dose escalation. The First in Human dose was 25 mg BID and there are a total of five pre-planned dose cohorts (25 mg BID; 50 mg BID; 100 mg BID; 200 mg BID and 400 mg BID). Subsequent to determining the OBD of single agent AUR103, combination studies with azacitidine and/or azacitidine/Venetoclax and/or ADCC competent antibodies will be studied in relevant tumor types. Results: As of the submission of the current abstract, both Cohort 1 and Cohort 2 have enrolled 3 patients each. There have not been any DLT or any Grade 3/4 AEs and also no evidence of any haemolytic anaemia of any grade in the first two cohorts. The reported AEs include Grade 1 itching (1/6), Grade 1 pain in legs (2/6), Grade 1 body ache (1/6), Grade 1 loss of appetite (1/6), Grade 1 shoulder pain (1/6), Grade 1 decrease in reticulocyte count (1/6), and Grade 2 drooping of eyelids (1/6). PK showed AUC0-12 of 1685 hr*ng/mL on Day 1 and 3465 hr*ng/mL on Day 15, in Cohort 1. The Cohort 2 PK showed a general dose proportionality with AUC0-12 of 2745 hr*ng/mL on Day 1 and 6669 hr*ng/mL on Day 15, respectively. Within each cohort, the variation in PK has been small. Enrolment in the 3rd cohort (100 mg BID) has been initiated. Summary/Conclusion: AUR103 is a novel First in Class small molecule inhibitor of CD47. The First in Human trial (AUR103-101; BHARAT) is currently enrolling. The preliminary safety in the first two cohorts appears commensurate with “lack of haemolysis” in non-clinical models. PK/PD results suggest that OBD should be reached by Cohorts 4 or 5. Updated results of safety, PK and PD will be presented at the meeting. Keywords: Phase I, AML
PB2558: REFERENCE VALUES FOR METHEMOGLOBIN LEVEL AND NADH-CYTOCHROME B5 REDUCTASE ACTIVITY IN TUNISIAN POPULATION.
Authors: Emna Bouatrous, Dorra Chaouachi, Boudrigua Imen, Menif Samia, Ouragini Houyem
Journal: HemaSphere (2023)

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Methemoglobin (MetHb) is a form of hemoglobin produced when the ferrous iron (Fe+2) is oxidized into ferric iron (Fe+3). MetHb is unable to bind oxygen, and its over production leads to methemoglobinemia characterized by impaired aerobic cellular metabolism, hypoxia, chocolate-brown colored blood and mucous membranes, cyanosis, and in rare cases to death. In normal physiological settings, MetHb remains below 1% through the NADH-cytochrome b5 reductase system, which converts the Fe+3 back to Fe+2. Deficiency in NADH-cytochrome b5 reductase enzyme, leads to MetHb accumulation, and therefore to recessive congenital methemoglobinemia (RCM). Reference values of normal range of methemoglobin and NADH-cytochrome B5 reductase are therefore crucial in the methemoglobinemia diagnosis. These reference intervals have been determined in several populations, but not in Tunisian population. Aims: The aim of this study was to establish the reference values of MetHb and NADH-cytochrome B5 reductase in Tunisian population. Methods: Our reference population consisted of 52 healthy hematology-based nonsmoking individuals. We carried out spectrophotometric measurements of MetHb level and NADH-cytochrome b5 reductase activity at 633 nm and 320 nm, respectively, according to the Dacie and Lewis method and Beutler. The results obtained were statistically analyzed by SPSS software to estimate the mean, standard deviation, and reference interval. This study was approved by the Pasteur Institute’s Biomedical Ethics Committee, Tunisia. Results: The sex ratio of the reference population was 0.52 and the mean age was 49 ± 15.55 Based on our results, the reference values are 1.89% ± 0.68 for methemoglobin and 24.42 ± 4.43 IU/g Hb for NADH cytochrome b5 reductase. Summary/Conclusion: Medical decision in diagnosis depends on the interpretation of laboratory test results compared with a reference interval. The International Federation of Clinical Chemistry (IFCC) recommends that every laboratory has to determine its own set of reference values using their own techniques and equipments. This work is the first step in the characterization of RCM in Tunisia. Keywords: Hemoglobin, Hemoglobinopathy
PB2647: USE OF EMICIZUMAB FOR THE TREATMENT OF ACQUIRED HEMOPHILIA A: A SYSTEMATIC REVIEW
Authors: Zainab Al-Housni, Andres Valenzuela, Essam Al Tawyan, Alfonso Iorio, Davide Matino
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Acquired Hemophilia A (AHA) is a rare disease that occurs due to the development of antibodies against FVIII, leading to severe bleeding complications with high morbidity and mortality. Emicizumab is a bispecific, monoclonal antibody that bridges activated factor IX (FIXa) and X (FX). It has shown to be effective in achieving hemostatic control in people with hemophilia A with FVIII inhibitors. Thus, it has been used off-label in the management of AHA. Aims: We conducted a systematic review on the use of Emicizumab for the treatment of AHA, focusing on the time required to achieve bleeding control. Methods: We conducted a comprehensive search in PubMed, EMBASE, Medline and The Cochrane Library from inception until January, 2023. Studies reporting cases of patients diagnosed with AHA that received at least one dose of emicizumab were included (Fig 1). Results: Eighteen studies were included in the final review for a total of 45 patients. The median age was 78 years (range: 21 – 93). The vast majority (75.6%) were males. Presenting bleeding symptoms were widely variable; the most common were subcutaneous bleeding and muscle hematomas. In forty patients the FVIII levels at diagnosis were ≤ 1% or undetectable. The median inhibitor level was 40 BU/mL (1.8 to 2000 BU/mL). Kaplan-Meier analysis showed that around 56% of patients have been reported to achieve bleed control in one day after the start of treatment and almost 90% of patients had no bleeding by day 5. (Fig 2). Side effects were infrequently reported; nevertheless, the treatment appeared to be well-tolerated Summary/Conclusion: Emicizumab appears to be an effective and safe hemostatic treatment for AHA. Bleeding control is rapidly achieved after initiating emicizumab. Clinical trials comparing emicizumab versus standard hemostatic agents are needed to confirm these findings.Keywords: Acquired factor VIII inhibitor, Acquired hemophilia
PB2069: ELTROMBOPAG WITH IMMUNO SUPPRESSIVE THERAPY IN SEVERE ACQUIRED APLASTIC ANEMIA IN CHILDREN AND ADOLESCENTS: A MONOCENTRIC EXPERIENCE
Authors: Nesrine Ben Sayed, Nadia Sassi, Haifa Regaieg, Rim Aidli, Wafa Chenbah, Bouraoui Ouni, Kmira Zahra, Yosra Ben Youssef, Abderrahim Khelif
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Severe acquired aplastic anemia (SAA) is a rare, life-threatening disorder. Immunosuppressive therapy with transfusion support represented the standard treatment. Recently eltrombopag was added to improve the outcome. Aims: This study aims to report the clinical and laboratory findings at the time of diagnosis, the treatment approach, and the outcome of children and adolescents with AA treated in our institution with eltrombopag and immunosuppressive therapy. Methods: We retrospectively evaluated 8 children and adolescents with (AA), treated with immunosuppressive therapy +eltrombopag and followed at the hematology department at Farhat Hached University hospital in Sousse-Tunisa between 2016 and 2022. Results: Eight patients, 5 males and 3 females with AA were analyzed. The mean age at diagnosis was 12 years (5 - 17 years). One patient had a type I diabetes. Another patient developed AA during treatment with isotretinoin. Infection was the most frequent reason for consultation in 5 patients followed by anemia (3 patients) and hemorrhagic signs in 2 patients. At the time of diagnosis, the average neutrophil count was 150/mm3, the Hb was 5.45 g/dl and the platelets count was 13400/mm3. According to the initial laboratory findings and the Camitta’s criteria, all patients were classified as very severe acquired aplastic anemia. All patients received equine anti-thymocyte globulin (ATGAM) + Cyclosporine associated with eltrombopag (150mg/day) and supportive care. Four patients achieved a complete response, a partial response in 2 cases. Two patients died of infectious complications. One of the2 patients who had a partial response underwent matched family donor allogenic stem cell transplantation (the donor weight initially was under 20 kg) and achieved a complete response, all 5 patients are transfusion independent and the 6th is currently in partial remission requiring often transfusion. No grade 3 or 4 toxicity was noted. The overall survival was 75% Summary/Conclusion: The addition of eltrombopag to standard immunosuppressive treatment was well tolerated and resulted in satisfactory hematological outcome in this single-institution experience. Keywords: Aplastic anemia, Immunosuppressive therapy, Children, Age
P1164: PEGARSPARGASE AND SINTILIMAB FOR NEWLY DIAGNOSED, ADVANCED STAGE NATURAL KILLER T-CELL LYMPHOMA, NASAL TYPE: AN OPEN-LABEL, SINGLE-ARM, PHASE 2 STUDY.
Authors: Jie Xiong, Shu Cheng, LI Wang, Peng-Peng Xu, Wei-LI Zhao
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Natural killer/T-cell lymphoma (NKTL) is a highly aggressive lymphoma that usually treated with intensive chemotherapy. Aims: To explore a more effective and less toxicity treatment for newly diagnosed stage III/IV NKTCL, we conducted a phase II study of pegarspargase and sintilimab chemo-free regimen. Methods: Patients with newly diagnosed stage III/IV disease and a performance status of 0 to 2 were eligible. Eligible patients were treated with induction treatment of pegaspargase 2500IU/m2 intramuscularly on day 1 and sintilimab 200mg intravenously on day 2 for 6 cycles, as well as maintenance treatment of sintilimab monotherapy. The primary end point was the complete remission (CR) rate at the end of induction treatment. The secondary end points include overall response rate (ORR), 2-year overall survival (OS) and progression-free survival (PFS), duration of remission (DOR), blood EBV DNA levels, treatment-related mortality (TRM), and adverse effect (AE) rate. Results: A total of 22 eligible patients were enrolled. The median age was 51 years (range, 14 to 74) and the male: female ratio was 16: 6. The CR and ORR after induction treatment was 59.1% (95% CI, 42.7 to 78.8) and 68.2% (95% CI, 47.3 to 83.6). 10 patients continued maintenance treatment of sintilimab and 2 patients underwent autologous hematopoietic stem-cell transplantation after induction treatment. With a median follow up of 18.2 months (range, 3.2 to 37.2) for PFS and 20.2 months (range, 4.7 to 39.2) for OS, the estimated 2-year PFS and OS for chemo-free cohort were 62.3% (95%CI, 33.5 to 81.5%) and 84.4% (95%CI, 58.3 to 94.8%), respectively. Grade 3/4 AEs were observed in 45% (n = 10) patients, including neutropenia (32%, n = 7), hypofibrinogenemia (18%, n = 4), leukopenia (9%, n = 2), anemia (5%, n = 1), thrombocytopenia (5%, n = 1), hypoalbuminemia (5%, n = 1), AST/ALT elevation (5%, n = 1), heart failure (5%, n = 1), which were manageable and led to no discontinuation of treatment. The comprehensive characterization of responders and non-responders were further investigated according to clinical parameters and exploratory multi-omic analysis. Dynamically monitoring of blood EBV DNA levels and the peripheral immune cell profile at diagnosed were potential prognostic markers. Summary/Conclusion: The chemo-free regimen is an effective treatment for newly diagnosed, advanced stage NKTCL with significantly prolonged PFS and OS, as well as reduced and manageable AEs. Keywords: Non-Hodgkin’s lymphoma
P1467: THE EMPLOYMENT OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS AFFECTED BY Β-THALASSEMIA: A MULTICENTER ANALYSIS FROM THE EXTENSION-MYOCARDIAL IRON OVERLOAD IN THALASSEMIA NETWORK (E-MIOT)
Authors: Simona Raso, Meloni Antonella, Anna Spasiano, Andrea Salvo, Maria Grazia Roberti, Valerio Cecinati, Angela Ciancio, Amalia Acquafredda, Ilaria Fotzi, Rosamaria Rosso, Marilena Serra, Costanza Bosi, Calogera Gerardi, Mariasanta Napolitano, Vincenzo Sucato, Rosario DI Maggio, Angela Vitrano, Filippo Cademartiri, Aurelio Maggio
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: Patients (PTs) with β-thalassemia (β-T) are at high risk of thrombosis due several factors including iron overload, splenectomy and chronic hemolysis. The increased thrombotic risk requires often the administration of antiplatelet and/or anticoagulant agents as treatment or prophylaxis of venous thromboembolism (VTE) and non-valvular atrial fibrillation (NVAF). Despite this, there is scarce specific evidence guiding the choice of anticoagulant treatment in the management of PTs with BT and there is limited experience regarding the use of direct oral anticoagulants (DOACs) which may deteriorate liver function, often already impaired in BT for secondary hemosiderosis. Aims: The main of the study was to evaluate the employment of DOACs in clinical practice. Methods: We herein have performed a multicenter retrospective analysis of patients with β-T experiencing VTE or NVAF, enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) Network study and actively treated with DOACs. Results are reported as median (Interquartile Range) for continuous variables and as frequencies n° (%) for categorical variables. Results: Fifty-five PTs were evaluated (Table 1). Thirty-two out of 55 PTs started DOACs as frontline anticoagulant treatment and 23 PTs were shifted from vitamin k antagonist (VKA) therapy. Apixaban and rivaroxabann were the most frequently adopted DOACs. The median time of treatment was 52.5 months (IQR,31.5-72), during follow-up 3 PTs developed superficial vein thrombosis (SVT) and 1 intestinal ischemia, major bleeding was not reported also in those subjects under concomitant antiplatelet drugs (Table 1). VTE recurrences under DOACs were treated low-molecular-weight-heparin (LMWH) for a mean of four weeks, DOACs resulted well tolerated and they were not discontinued or dose-reduced in any subject Summary/Conclusion: We here report the first available comprehensive evaluation of DOACs in BT. However, in our experience there were no adverse events reported and no need of dose modification. Anticoagulant therapy with DOACs in PTs with βT is well tolerated, apparently safe, without recurrences of major thrombotic events and significant bleeding complicationsKeywords: Thalassemia
PB1818: PROGNOSTIC VALUE OF NEOPLASTIC INFLAMMATION AND CYTOKINES IN THE COURSE OF ACUTE MYELOID LEUKEMIA WITH MATURATION
Authors: Vira Barilka, Olha Shalay, Volodymyr Matlan, Sofiya Prymak, Vasyl Novak
Journal: HemaSphere (2023)

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Course of acute myeloblastic leukemia (AML) with maturation, subtype M2 (AML M2); (FAB 2016), has an individual behavior and may depend on the an indicators of neoplastic inflammation, leukocytosis/cytopenia, lymphocytosis, blasts, cytokines in the peripheral blood (PB) of AML M2 patients (pts). This was confirmed by the anti-inflammatory effect of glucocorticoids, which improves the effectiveness of AML treatment. In addition, there are few reports on the role and indicators of neoplastic inflammation in the course of AML M2. Aims: To determine the prognostic value of the an indicators of neoplastic inflammation and cytokines, TNF and TGFβ1, in the course and survival of AML M2 pts. Methods: We examined of 14 untreated AML M2 pts; median age 68,5 (range 47 – 76) years and 10 AML pts without maturation (ALM M1) as the compared group (median age 63, range 26 – 81 years). The control group consisted of 15 healthy individuals. All AML pts (n=24) had blasts in PB (60.90 ± 7.78) ×10 9/l. The concentration of TNF and TGFβ1, were detected in the plasma and 24-h supernatants of peripheral blood mononuclear cells mixed with blasts (PBMC), by biological methods. Indicators of inflammation were detected in the hemograms of AML pts. The statistical processing were determined in the Exel program. Results: The AML M2 pts had a higher number of blasts, leukocytes and a lower content of mature neutrophils and lymphocytes in the hemogram, than in AML M1 pts. It could affect on the PBMC production of cytokines and the survival of AML pts. The concentration of TNF in the supernatants of PBMC of AML M2 pts was significantly higher than in AML M1 and control in both cases; p˂0.001. Detected a direct correlation between the TNF in the plasma of AML M2 pts and the number of blasts (r= 0.48) and an inverse correlation between the number of blasts and the TGFβ1 in the plasma (r= - 0, 36), as well as with the concentration of the TGFβ1 in the supernatants of PBMC (r= - 0.59) of the AML M2 pts. The median survival of AML M2 pts was three times shorter than in the AML M1 pts. An inverse correlation was established between survival and TNF plasma of AML M2 pts (r= - 0.28). To compare, the survival of AML M1 pts was positively correlated both of TNF and TGF in plasma r= 0.92 and r= 0.42, respectively. Summary/Conclusion: The indicators of neoplastic inflammation, cytokines, TNF, TGFβ1, have different pathogenetic effects on the survival both of AML M2 and AML M1 pts. In addition, they not only identify of AML M2 pts as a high-risk group, but provide well-defined prognostic markers for future clinical trials and evaluation of survival in AML pts too. Keywords: Acute myeloid leukemia, Cellular immunity, Cytokine, Prognostic
PB2599: THE FREQUENCY OF PHENOTYPES OF THE MNS, KIDD, DUFFY SYSTEMS IN PATIENTS OF THE HEMATOLOGY CLINIC
Authors: Anna Yovdiy, Maria Smolnikova, Elena Poponina, Philip Philip
Journal: HemaSphere (2023)

Topic: 31. Transfusion medicine Background: Oncohematological patients are at risk of developing post-transfusion complications. The likelihood of immunization against red blood cells antigens increases with the number of transfusions. In order to prevent alloimmunization and post-transfusion complications in the hematology clinic of the KRIHBT, a register of donors typed according to red blood cells antigens MNS, Kidd, Duffy was created. The registry should provide patients at risk with wide range of antigens compatible red blood cells. Aims: Comparative analysis of the prevalence of phenotypes of the MNS, Kidd, Duffy systems in patients of the hematology clinic. Methods: Blood tests of patients were carried out using immunohematological analyzers and reagents IH-1000 BioRad (USA), Ortho Vision (USA). MNS, Kidd, Duffy antigens were typed in patients with anti- red blood cells antibodies or in need of long-term transfusion therapy. Pearson’s X2 was used for statistical data processing. Results: Of the 118 patients referred for typing of MNS antigens, Kidd, Duffy 72 (61%) were diagnosed with multiple myeloma, 23 (20%) with myelodysplastic syndrome, 6 (5%) with chronic myelocytic leukemia, 5 (4%) with lymphoma, and 12 (10%) with other diseases of the blood system. 71 (60%) patients had polyspecific antibodies, 66 of which were due to monoclonal anti-CD38 (Daratumumab) antibodies; 9 (8%) patients had specific anti- red blood cells antibodies; 7 (6%) had antibodies of unknown specificity; in 31(26%) patients, anti- red blood cells antibodies were not detected. The prevalence of phenotypes of the MNS, Kidd, Duffy systems in oncohematological patients and blood donors is presented in Table.Summary/Conclusion: No significant differences in the frequency of phenotypes of the MNS, Kidd, Duffy systems in patients of the hematology clinic and blood donors living in the European territory of Russia (Butina 2021), in Europe and America (Shaz B.H. 2013) were found. Data on the distribution of transfusion-dangerous red blood cells antigens among patients in the hematological clinic are of great importance for improving the immunohematological provision of hemocomponent therapy for patients at risk of developing post-transfusion complications. Keywords: Red blood cell, Phenotype
PB2550: EXPLORATION OF B-CELL RECEPTOR AND T-CELL RECEPTOR REPERTOIRES REVEALS DISTINCT MECHANISMS IN PURE RED CELL APLASIA, AUTOIMMUNE HEMOLYTIC ANEMIA AND APLASTIC ANEMIA
Authors: Ruoxi Zhang, Bing Han
Journal: HemaSphere (2023)

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Pure red cell aplasia (PRCA), autoimmune hemolytic anemia (AIHA) and aplastic anemia (AA) are erythrocyte diseases caused by immune-mediated destruction of erythrocyte or erythroid progenitor cells. However the mechanism is not clear. Aims: This study aimed to investigate changes related to autoimmune in the B-cell receptor (BCR) and T-cell receptor (TCR) repertoires and explain the varied involvement of T and B cells. Methods: Patients with newly diagnosed primary PRCA, AIHA, and AA were enrolled. Healthy individuals with matched age and sex served as the normal control (NC). Next-generation immunosequencing analysis of BCR and TCR repertoires of peripheral blood genomic RNA was performed. Gene usage, length, encoded amino acid sequence, sequence diversity and disease-associated BCRs and TCRs were determined. Results: 10 PRCA, 10 AIHA, 10 AA and 7 NC were finally enrolled. For BCR and TCR repertoire metrics, compared with NC, PRCA, AIHA and AA showed uniform characteristics in the VDJ gene usage distribution, complementarity-determining regions 3 (CDR3) amino acids usage and sequence diversity. PRCA, AIHA and AA all had disease-specific CDR3 sequences in both BCR and TCR. AIHA and AA had higher clonal expression amplification in BCR compared with NC (p>0.05). BCR light chain usage was significantly different in the three disease groups compared with NC (p>0.05). Regarding the changes in BCR and TCR related to the recognition of autoimmune antigens, PRCA showed more changes in TCR repertoire metrics, but AIHA showed more changes in BCR repertoire metrics, whereas AA showed significant changes in both BCR and TCR repertoire. Summary/Conclusion: PRCA, AIHA and AA had specific BCR and TCR repertoire distributing to the autoimmune antigen recognition. PRCA was mainly T cell-mediated, whereas B cells were implicated in AIHA. Both B and T cells participated in the mechanism of AA. Keywords: Pure red cell aplasia, Aplastic anemia, Autoimmune hemolytic anemia (AIHA)